ABSTRACT Significance: Though highly effective in changing the course of the global HIV epidemic, current Antiretroviral Therapy (ART) fails to eradicate the infection completely. This had lead to the emergence of drug-resistant mutant strains, the phenomenon of latent disease and a number of adherence and toxicity issues associate with long-term therapy. Novel compounds that inhibit transcription from integrated viral genomes, thereby preventing the production of viral particles from stable viral reservoirs, present a valuable and differentiated therapeutic potential in the treatment of HIV. Tat, a potent transactivator of HIV gene expression essential for the synthesis of full-length transcripts of the integrated viral genome by RNA polymerase II, is a highly sought after transcription target for the treatment of HIV. Innovation: Didehydro-cortistatin A (dCA), a representative of the cortistatin class of compounds, has demonstrated significant potential as a potent inhibitor of Tat. Preliminary Data: dCA has been shown to inhibit acute HIV-1 replication, has demonstrated additive effect of viral inhibition when combined with ART, and has been found to highly impact latent viremia in CD4+T cells of virally suppressed patients receiving ART for at least three years. However, dCA has been shown to have off target activity that impacts it?s safety profile in HIV therapy, including potent anti-angiogenesis effect. Specific Aims: The goal of this proposal is the design of a lead cortistatin agent that retains Tat inhibition activity, has drug-like properties, and has a desirable safety and tolerability profile including the reduction of off-target antiangiogenesis activity. Specific Aim 1. Optimization of key coupling step to enable the large scale synthesis of dCA: : In the Baran total synthesis of dCA the final step involves a Stille coupling reaction using 50% loading of palladium catalyst while only providing a 50% yield of dCA. Screening new palladium catalysts, reaction temperatures, solvents, reaction times, concentration and lowering catalyst loading will be carried out to increase the efficiency of this reaction. Specific Aim 2A. Discovery of Alternative Scaffolds by modification of ?Steroid Body?: The Cost of Goods (COGS) to produce large quantities of dCA is a significant limiting factor that could potentially derail the advancement of this compound into clinical trials. It is therefore prudent to discover alternative ?Steroid Body? chemical scaffolds that can be synthesized readily on large scales. Specific Aim 2B. Optimization of Drug metabolism, Drug-Drug Interactions and Oral Bioavailability: All truncated analogs prepared above will be evaluated in microsomal stability assays, metabolic soft spots will be identified using MS/MS analysis and design optimization will be driven towards molecules that display potent TAT inhibition while being stable to liver microsomes (low hepatic clearance). At the end of this Phase I study we expect to (a) have highly efficient reaction conditions to carry out the key coupling reaction smoothly; (b) identify second generation ?Steroid Body?-chemical scaffold displaying potent inhibition of acute HIV replication via Tat binding, good oral bioavailability, minimum drug interaction potential and ready for IND enabling studies.